Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The antitumor activity of interleukin (IL)-12, a naturally occurring cytokine, has been demonstrated in several murine solid tumors. Animals bearing established B16 melanoma or MB-49 bladder carcinoma were used to study the most effective scheduling of recombinant murine IL-12 (rmIL-12), along with systemic chemotherapy. rmIL-12 (0. 45, 4.5, or 45 microgram/kg) was more effective as a single agent when administered to mice bearing the MB-49 bladder carcinoma at the highest dose for 11 doses rather than for 5 doses. In combination with chemotherapy (Adriamycin, cyclophosphamide, or 5-fluorouracil), rmIL-12 administration did not increase the toxicity of the chemotherapy, and there was increased antitumor activity with each rmIL-12-drug combination. Administering rmIL-12 (45 microgram/kg) on days 4-14, along with Adriamycin, cyclophosphamide, or 5-fluorouracil on days 7-11, resulted in 2.2-2.7-fold increases in tumor growth delay, compared with the chemotherapy alone against the primary tumor, and a marked decrease in the number of lung metastases on day 20. Because the B16 melanoma grows more slowly than the MB-49 bladder carcinoma, allowing multiple courses of chemotherapy, cyclophosphamide could be administered. The rmIL-12 (45 microgram/kg)-cyclophosphamide combination regimen that was most effective overlapped 2 days with the terminal portion of the chemotherapy treatment. There was a parallel increase in the response of the primary tumor and metastatic disease to the lungs. Administration of rmIL-12 to animals bearing the MB-49 bladder carcinoma or the B16 melanoma was compatible with coadministration of chemotherapy at full dose without additional toxicity.
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PMID:Optimal scheduling of interleukin 12 and chemotherapy in the murine MB-49 bladder carcinoma and B16 melanoma. 981 57

It was previously reported that polysaccharides (PL) isolated from Phellinus linteus strongly stimulated cell-mediated and humoral immunity. This study was undertaken to investigate the immunochemotherapeutic activity of PL against tumor growth and metastasis. PL alone significantly prolonged the survival rate of B16F10-implanted mice, inhibited tumor growth in NCI-H23-implanted nude mice, and reduced the frequency of pulmonary metastasis of B16F10 melanoma. Adriamycin significantly inhibited tumor growth, but only slightly inhibited metastasis. The combination therapy with PL and adriamycin was more effective in inhibiting tumor growth, but not metastasis. PL did not induce direct toxicity in cancer cells, which is characteristic of immunotherapeutics. In conclusion, PL might be of use in immunochemotherapy of cancer because of its effective activities on tumor growth and metastasis through the immunopotentiation of the patients without toxicity.
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PMID:The inhibitory effect of polysaccharides isolated from Phellinus linteus on tumor growth and metastasis. 1010 97

Various tumor-associated antigens have been identified as carbohydrates bound to lipids or to proteins expressed on tumor cell membranes. We prepared tumor-specific immunoliposomes by coupling anticarbohydrate antibodies, such as antiganglioside G(M3) antibody (DH2) or anti-Le(x) antibody (SH1), to polyethylene glycol (PEG)-coated liposomes. In vitro and in vivo targetability of anti-G(M3) and anti-Le(x) immunoliposomes to B16BL6 mouse melanoma cells and HRT-18 human colorectal adenocarcinoma cells were monitored with a fluorescence microscopy, and analyzed by biodistribution assay of the immunoliposome in mice bearing the tumor tissues. The antibody coupling to the PEG liposomes did not greatly diminish the circulation time of the liposome in the C57BL/6 mouse model. In vitro cytotoxicity of doxorubicin encapsulated in liposomes was enhanced by antibody coupling, but still behind free doxorubicin. However, in vivo antitumor therapeutic efficacy of doxorubicin encapsulated in the immunoliposomes was far greater than the free drug or in conventional liposomes. Doxorubicin encapsulated in anti-G(M3) immunoliposomes was able to reduce in vivo tumor growth and metastasis of B16BL6 mouse melanoma cells more greatly than any other formulations of the drug. This study suggests that tumor-associated antigens can be good target molecules for tumor-specific delivery of liposomal drugs or other synthetic drug delivery systems.
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PMID:Sterically stabilized anti-G(M3), anti-Le(x) immunoliposomes: targeting to B16BL6, HRT-18 cancer cells. 1045 Oct 27

We previously reported antiangiogenic activity of roxithromycin and clarithromycin, 14-membered ring macrolide antibiotics. In the present study, we examined the antitumor effects of roxithromycin and clarithromycin, alone and in combination with several cytotoxic drugs, on mouse B16BL6 melanoma cells in vivo and in vitro. Both roxithromycin and clarithromycin potentiated the inhibition of tumor growth induced by cyclophosphamide, cis-diamminedichloroplatinum(II), Adriamycin and vindesine in vivo. However, neither roxithromycin nor clarithromycin, altered the cytotoxicity of 4-hydroperoxycyclophosphamide, cis-diamminedichloroplatinum(II), Adriamycin or vindesine in an in vitro cell proliferation assay. These results suggest that the antiangiogenic activity of roxithromycin and clarithromycin may provide beneficial effects in combination with cytotoxic therapies against solid tumors.
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PMID:Roxithromycin and clarithromycin, 14-membered ring macrolides, potentiate the antitumor activity of cytotoxic agents against mouse B16 melanoma cells. 1066 84

S16020-2, a new olivacine derivative and a topoisomerase II inhibitor, has recently entered clinical trials. New analogues and derivatives have been synthesized from the S16020-2 compound. Preliminary data indicate that S30972-1, one of these S16020-2 derivatives, may exhibit a comparatively higher level of antitumor potency associated with an improved therapeutic index than does S16020-2. The antitumor activities of S16020-2 and S30972-1 were therefore characterized both in vitro and in vivo, with Adriamycin and etoposide chosen as reference compounds. The in vitro data show that S30972-1 is a topoisomerase II inhibitor, mediating its activity through an ATP-dependent mechanism such as S16020-2. The two olivacine derivatives exhibited similar activities in vitro at the levels of the global growth of six human cancer cell lines, of the induction of apoptosis, and of the G2 cell cycle phase arrest. The in vivo antitumor activity characterization included the use of two murine leukemia types (P388-LEU and L1210-LEU), two murine lymphoma-like models (P388-LYM and L1210-LYM), two mammary adenocarcinomas (MXT-HI and MXT-HS), and one melanoma (B16). The data show that S30972-1 is actually more efficient in vivo than S16020-2, a feature that may relate to the fact that S30972-1 is less toxic than S16020-2. The S30972-1 compound exhibited in vivo a level of antitumor activity that was also actually higher than that exhibited by Adriamycin and similar to that exhibited by etoposide.
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PMID:In vitro and in vivo pharmacological characterizations of the antitumor properties of two new olivacine derivatives, S16020-2 and S30972-1. 1099 72

Adriamycin (ADR), one of the major antitumor agents used for the clinical treatment of a wide variety of human cancers and its glutathione(GSH)-conjugated adduct, ADRIGLU, induced apoptosis in K562 erythroleukemia and TVM-A12 clone 2 melanoma human cell lines. We have previously reported that ADR has nuclear localization and that ADRIGLU localizes exclusively in the cytoplasm. During ADR or ADRIGLU treatment, significant depletion of the cell energy state, demonstrated by a reduction in high-energy phosphates (ATP and GTP) and a decrease in energy charge potential (ECP), were recorded between 2 hours and 24 hours, by HPLC analysis. Transmission electron microscopy also revealed that between 2 hours and 24 hours of ADR or ADRIGLU treatment, mitochondria underwent evident morphological changes, from an initial "high amplitude swelling state" to a "shrinkage state" and finally, in early apoptotic cells, to an "abnormal shrinkage state", in which a marked accumulation of pycnotic mitochondria was also observed. Confocal microscopic analysis, using the potential-sensitive dye JC-1, showed that inhibition of cell energy metabolism was preceded by a rapid decrease in mitochondrial transmembrane potential (delta psi m). With the progression of exposure time, the early depolarization of the mitochondrial membrane was followed by a transient reversion to normal delta psi m until, in apoptotic cells, almost all mitochondrial subpopulations appeared to be hyperpolarized. Our results indicated that mitochondria are actively involved in anthracycline-induced programmed cell death, suggesting a novel mechanism that may be common to all forms of apoptosis.
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PMID:Modifications of mitochondria in human tumor cells during anthracycline-induced apoptosis. 1113 38

Activating transcription factor 2 (ATF2) and its kinase, p38, play an important role in the resistance of melanoma to radiation and chemotherapy. Whereas ATF2 up-regulates the expression of tumor necrosis factor alpha, which serves as a survival factor in late-stage melanoma cells, p38 attenuates Fas expression via inhibition of nuclear factor-kappaB. We investigated whether ATF2-derived peptides could be used to alter the sensitivity of human melanoma cells to radiation and chemical treatment. Of four 50-amino acid peptides tested, the peptide spanning amino acids 50-100 elicited the most efficient increase in the sensitivity of human melanoma cells to UV radiation or treatment by mitomycin C, Adriamycin, and verapamil, or UCN-01, as revealed by apoptosis assays. Sensitization by ATF2 peptide was also observed in the MCF7 human breast cancer cells but not in early-stage melanoma or melanocytes, or in in vitro-transformed 293T cells. When combined with an inhibitor of p38 catalytic activity, cells expressing amino acids 50-100 of ATF2 exhibited an increase in the degree of programmed cell death, indicating that combined targeting of ATF2 and p38 kinases is sufficient to induce apoptosis in late-stage melanoma cells. The ability of the peptide to increase apoptosis coincided with increased cell surface expression of Fas, which is the primary death-signaling cascade in these late-stage melanoma cells. Overall, our studies identified a critical domain of ATF2 that may be used to sensitize tumor cells to radiation and chemical treatment-induced apoptosis and that can induce apoptosis when combined with inhibition of ATF2 kinase, p38.
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PMID:Activating transcription factor 2-derived peptides alter resistance of human tumor cell lines to ultraviolet irradiation and chemical treatment. 1123 88

A high-throughput screening assay was designed to select compounds that inhibit the growth of cultured mammalian cells. After screening more than 60,000 compounds, A-105972 was identified and selected for further testing. A-105972 is a small molecule that inhibits the growth of breast, central nervous system, colon, liver, lung, and prostate cancer cell lines, including multidrug-resistant cells. The cytotoxic IC50 values of A-105972 were between 20 and 200 nM, depending on the specific cell type. The potency of A-105972 is similar in cells expressing wild-type or mutant p53. A majority of cells treated with A-105972 were trapped in the G2-M phases, suggesting that A-105972 inhibits the progression of the cell cycle. Using [3H]A-105972, we found that A-105972 bound to purified tubulin. Unlabeled A-105972 competed with [3H]A-105972 binding with an IC50 value of 3.6 microL. Colchicine partially inhibited [3H]A-105972 binding with an IC50 value of approximately 90 microM, whereas paclitaxel and vinblastine had no significant effect. Tumor cells treated with A-105972 were observed to contain abnormal microtubule arrangement and apoptotic bodies. DNA ladder studies also indicated that A-105972 induced apoptosis. A-105972 caused a mobility shift of bcl-2 on SDS-PAGE, suggesting that A-105972 induced bcl-2 phosphorylation. A-105972 treatment increased the life span of mice inoculated with B16 melanoma, P388 leukemia, and Adriamycin-resistant P388. These results suggest that A-105972 is a small molecule that interacts with microtubules, arrests cells in G2-M phases, and induces apoptosis in both multidrug resistance-negative and multidrug resistance-positive cancer cells. A-105972 and its analogues may be useful for treating cell proliferative disorders such as cancer.
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PMID:Identification and characterization of A-105972, an antineoplastic agent. 1124 55

Adriamycin (ADM), an anthracycline anticancer agent, is selectively stored in the nuclei of a variety of proliferating cells, but the precise mechanism of specific nuclear transport of ADM is not well known. Recently, we demonstrated that ADM shows high binding affinity to the cytoplasmic proteasomes of L1210 mouse leukemia cells and that taken up ADM by the cells selectively binds to proteasomes. Nuclear targeting of proteasome in proliferating cells may be mediated by the nuclear localization signals that are found in several of the alpha-type subunits of the 20S proteasome. To confirm nuclear transport of the ADM-proteasome complex, we synthesized a photoactive ADM analogue, N-(p-azidohenzoyl)-ADM, and generated a photoaffinity-labeled proteasome complex. The 26S proteasome purified from the cytosol of L1210 cells had a high affinity to N-(p-azidobenzoyl)-ADM. SDS-PAGE analysis of the photoaffinity-labeled proteasome showed that low molecular weight bands (approximately 21-31 kDa) of 20S proteasome had the highest photoaffinity. The photoaffinity-labeled proteasome was distributed in the cytoplasm and nuclei of digitonin-permeabilized L1210 and B-16 mouse melanoma cells in the presence of the cytosolic fraction and ATP. The rate of nuclear translocation of the proteasome was low in the absence of ATP. These results suggest that the proteasome is a specific translocator of ADM from the cytoplasm to the nucleus and that 20S proteasome components are the dominant ADM-binding sites. The nuclear transport of ADM-proteasome complex is regulated by an ATP-dependent nuclear pore-mediated mechanism.
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PMID:Mechanism of specific nuclear transport of adriamycin: the mode of nuclear translocation of adriamycin-proteasome complex. 1128 16

A drug-loaded tumor cell (DLTC) system has been developed for lung metastasis-targeting drug delivery. Doxorubicin was loaded into B16-F10 murine melanoma cells (96 microg/10(6) cells). The loading process led to the death of all the carrier cells. The diameter of DLTC was 15.03+/-2.36 microm (mean +/- SD). The amount and rate of doxorubicin being released from the DLTC mainly depended on the drug loading and carrier cell concentration. Over a 6-month storage in phosphate buffered saline (PBS) at 4 degrees C, the decrease in intracellular drug concentration and the carrier cell number were less than 25% and 5%, respectively. After a bolus injection of 30 microg doxorubicin in either DLTC form or free solution into the mice tail veins, drug deposit in the lung from DLTC was 3.6-fold of that achieved by free drug solution. The latter resulted in higher drug content in liver and spleen. Extensive trypsinization of DLTC reduced its lung targeting effect by 30%, and the density of surface adhesion molecule GM3 on DLTC surface by 25%. In conclusion, this DLTC system demonstrated a lung-targeting activity that may be partially attributed to its specific surface characteristics.
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PMID:A cell-based drug delivery system for lung targeting: I. Preparation and pharmacokinetics. 1140 Aug 64


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